Pain is a sensory experience distinct from sensations of touch, pressure, heat and cold. It is often described by sufferers in such terms as bright, dull, aching, pricking, cutting or burning and is generally considered to include both the original sensation and the reaction to that sensation. It can be classified by the duration as either acute or chronic, or by the cause as either nociceptive, in that it is being caused by the ongoing activation of pain receptors or neuropathic in that it is caused by changes in the nervous system.
Nociceptive pain, also called acute pain, is caused by activation of the nocioceptors, sensory neurons that respond to stimuli which can cause tissue damage such as sprains, bone fractures, burns, bumps, bruises, or inflammation. Nociceptive pain usually resolves once the condition that precipitated it is healed and is generally responsive to opioids and traditional analgesics.
Neuropathic pain syndromes are linked by injury or damage to either the peripheral and/or the central nervous system. The symptoms associated with neuropathic pain conditions include allodynia (painful response to a non-noxious stimulus, such as the touch of clothing), hyperalgesia (heightened or extreme sensitivity to painful stimuli), paraesthesias (abnormal sensations such as tingling, burning, pricking or tickling), hyperesthesia (enhanced sensitivity to a natural stimuli), and dysesthesias (disagreeable sensations produced by ordinary stimuli). Neuropathic pain is generally nonresponsive or only partially responsive to conventional analgesic regimens, such as non-steroidal anti-inflammatory agents, (e.g., ibuprofen; acetaminophen; aspirin; celecoxib) and opioids. Therapeutic methods currently used to treat neuropathic pain include neurosurgery treatments such as nerve block and epidural spinal cord electric stimulus, tricyclic antidepressants (e.g., amitriptyline), intrathecal administration of baclofen, anti-epileptics, milnacipran, duloxetine, pregabalin, and gabapentin.
Pain can be acute, lasting less than thirty days or chronic, lasting more than six months. One in five people suffer from moderate to severe chronic pain, and one in three people are unable or less able to maintain an independent lifestyle due to their pain. It has been reported that between one-half and two-thirds of people with chronic pain are less able or unable to exercise, enjoy normal sleep, perform household chores, attend social activities, drive a car, walk or have sexual relations.
1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane was previously described in U.S. Pat. Nos. 4,131,611, 4,196,120, 4,231,935, and 4,435,419.
(1R,5S)-(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane of Formula I, below,
is a stereoisomer of 1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane. (1R,5S)-(+)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane is described as an anti-depressant in U.S. Pat. No. 7,098,229.
Administration of a racemic, i.e., 50:50, mixture of the (+)- and the (−)-enantiomer of any drug, for example (±)-1-(3,4-dichlorophenyl)-3-azabicyclo[3.1.0]hexane, to a patient can be disadvantageous. First, the racemic mixture might be less pharmacologically active than one of its enantiomers, rendering racemic drugs inherently inefficient. Second, the racemic mixture may be more toxic to a patient than one of its enantiomers, so that administration of a racemic mixture can lead to undesirable side effects in a patient.
Many metabolic routes of elimination may be inhibited or induced by concomitant drug treatment. Metabolic drug-drug interactions (DDIs) may cause substantial changes—an order of magnitude or more decrease or increase in the blood and tissue concentrations of a drug or metabolite—and may affect the extent to which toxic or active metabolites are formed. These large changes in exposure may alter the safety and efficacy profile of a drug and its active metabolites. The risk of DDIs is large because it has been reported that 20.8% of people in the U.S. use three or more drugs per month and 10.2% use 5 or more drugs per month. Serious adverse events may be attributable to DDIs. Cytochrome P450 (CYPs) enzyme isoforms, which catalyze oxidative reactions, account for the metabolism of 75% of all drugs, and in particular, about 80% of drugs cleared by CYPs are metabolized by four CYP isoforms—CYP3A4, CYP2D6, CYP2C9 and CYP2C19. Thus, these four CYPs are potential candidates for DDIs. In addition, CYP2D6 and CYP2C19 are polymorphic and have fast metabolizing and slow metabolizing alleles, which may alter the rate of drug metabolism and plasma drug levels. Physicians must routinely consider potential DDIs and metabolic pathway(s) when selecting treatments.
Few agents and combinations of agents currently prescribed for the treatment of neuropathic pain are fully effective. Additionally, the agents and combinations of agents currently prescribed for chronic pain have limited therapeutic value, losing their efficacy with extended use, and frequently have undesirable side effects including, for example, cognitive changes, sedation, nausea, liver damage, and, in the case of narcotic drugs, respiratory depression, constipation, and addiction. Further, the agents and combinations of agents currently prescribed for chronic pain may be contraindicated in certain patient populations. For instance, as with other opiate-based painkillers, chronic use of codeine can cause physical dependence. In addition, central to the therapeutic action of codeine is its conversion by the cytochrome P-450 metabolizing enzyme 2D6 (CYP2D6) to morphine. Up to 10% of the Caucasian population, however, may have a polymorphism in the metabolizing enzyme that results in the inability to convert codeine to morphine, thus not gaining any analgesia from codeine. Such patients are known as codeine non-responders. Conversely, some people, known as ultrarapid metabolizers, achieve higher-than-expected serum levels of morphine which can lead to side effects such as abdominal pain. In patients treated with duloxetine (Cymbalta®), a serotonin-norepinephrine reuptake inhibitor (SNRI) that is mainly eliminated through hepatic metabolism, there have been reports of hepatic failure, sometimes fatal, and duloxetine should ordinarily not be used in patients with hepatic insufficiency. Elimination of acetaminophen is principally by liver metabolism (conjugation) and subsequent renal excretion of metabolites. Acetaminophen may cause serious liver damage if higher doses are used or if the acetaminophen metabolizing capacity of the liver is overwhelmed as with acetaminophen co-administration with ethanol or when fasting.
Some common analgesics are known to be substrates and/or inducers and/or inhibitors of cytochrome P450 isoforms. Patients taking these analgesics may be at a greater risk of experiencing adverse drug-drug interactions. Analgesics that may pose a risk of drug-drug interactions include, e.g., acetaminophen (CYP1A2 and CYP2E1 substrate), naproxen (CYP1A2 and CYP2C9 substrate), indomethacin (CYP2C19 substrate and inhibitor), diclofenac (CYP2C9 substrate), and celecoxib (CYP2C9 substrate and CYP2D6 inhibitor). CYP inhibitors and inducers that could adversely interact with these analgesics include ciprofloxacin, cimetidine, and fluvoxamine (CYP1A2 inhibitors); amiodarone, fluconazole, fluvastatin, isoniazid, lovastatin, paroxetine, sertraline, zafirlukast, and metronidazole (CYP2C9 inhibitors); bupropion, fluoxetine, paroxetine, quinidine, duloxetine, sertraline, cimetidine, chlorpromazine, diphenhydramine, and ranitidine (CYP2D6 inhibitors); omeprazole and insulin (CYP1A2 inducers); phenobarbital and carbamazepine (CYP2C9 inducers); dexamethasone (CYP 2D6 inducer); and rifampin (CYP1A2, CYP2C9 and CYP2D6 inducer).
Amitriptyline, which may be used to treat neuropathic pain, is a CYP1A2 and CYP2D6 substrate, and can adversely interact with monoamine oxidase inhibitors, anticholinergics, antipsychotics, cimetidine, dilsulfiram, and serotonergic agents (e.g., SSRIs, such as fluoxetine, sertraline, paroxetine and escitalopram).
Further, while it has been reported that as many as 28% of people experiencing chronic pain turn to alcohol to alleviate their suffering, using common analgesics with alcohol may place people at risk for a number of harmful health consequences. For instance, mixing alcohol and acetaminophen may cause acute liver failure and the prescribing information for duloxetine indicates that duloxetine should not be prescribed to patients with substantial alcohol use because duloxetine and alcohol may interact to cause liver injury.
Medications that include combinations of agents for chronic pain may include the undesirable side effects of each agent. For instance, in 2011, the FDA required a boxed warning that highlights the potential for severe injury on all prescription acetaminophen products. Prescription acetaminophen products include acetaminophen with other active ingredients. Acetaminophen with codeine also includes a warning that codeine can produce drug dependence of the morphine type and, therefore, has the potential for being abused.